Practical Oncology Principles of Chemotherapy Wendy Blount DVM

Practical Oncology Principles of Chemotherapy Wendy Blount, DVM

Indications for Chemotherapy § Systemic or metastatic disease that is chemo responsive • local control (surgery, radiation therapy) isn’t adequate • Cure is rare (TVT is an exception, MCT is possible) • Remission or prolonged stable disease is likely • Months to years • Prepare owners for relapse that will ultimately be unmanageable § Neo adjuvant therapy • Reducing size of large, localized tumor prior to surgery

Metronomic Therapy § Fewer side effects than high dose treatment § More effective when minimal gross disease § Cyclophosphamide and piroxicam to prevent recurrence of sarcomas • Cyclophosphamide 10 mg/m 2 PO SID or QOD • Piroxicam 0. 3 mg/kg PO SID or QOD § Take care that the pet is not also on prednisone § Low dose chlorambucil is also considered metronomic • Chlorambucil 4 mg/m 2 PO SID § Some use Palladia at 2 mg/kg 3 x weekly (MWF)

Side Effects § Make sure clients understand that chemo protocols for animals are much less aggressive than for people • Side effects are assumed to be present and possibly severe for people • Many pets who undergo chemotherapy have infrequent side effects that are often mild § Chemo drugs kill or harm cells that divide rapidly • Gastrointestinal tract, bone marrow, skin and hair § The most common side effects are gastrointestinal, pancytopenias (mostly WBC)

Side Effects GI Toxicity – vomiting, diarrhea, poor appetite § Direct stimulation of the chemoreceptor trigger zone • 24 48 hours after chemo § Direct damage to epithelial cells • 3 5 days after chemo § Can vary from a few soft stools to parvovirus like disease § Dispense Cerenia and Metronidazole at the first treatment if you anticipate a problem with getting the meds on the day needed

Side Effects GI Toxicity – vomiting, diarrhea, poor appetite § >50% have signs of nausea at days 3 5 after chemo, and is self limiting • • Licking lips, Stepping away from food Diarrhea as well This is why we dispense meds Educate clients as to signs of nausea § Cerenia® works especially well (25 x) substance P inhibitor at NK 1 receptor (Emend® $100 per pill) • 5 HT 3 antagonist Zofran® ($35), Kytril® ($45), Anzemet® ($75)

Side Effects Bone Marrow Toxicity § Direct damage to stem cells • Neutrophils have shortest life, so they are affected first • Then other WBC, platelets and RBC § Delay chemo if Neutrophils <2, 000/ul • recheck CBC 3 7 days § Antibiotic therapy if fever or neutrophils <1, 000/ul § GCSF (Neupogen®) if neutrophils <500/ul § IV fluids and IV antibiotics only if septic • Placing an IV catheter in an asymptomatic

Side Effects Bone Marrow Toxicity § Delay chemo if platelets <50, 000, unless Tpenia is thought to be caused by neoplasia § If cytopenia, delay treatment by 3 7 days and reduce dose by 20 25% when resumed • Lomustine*, doxorubicin, cyclophosphamide*, chlorambucil delay at least 7 days § Most develop mild anemia that resolves when stopped CBC the day of and prior to every chemo dose Draw from the jugular vein

Side Effects Bone Marrow Toxicity Nadirs – recovery usually within 7 days (*these drugs longer) § Not usually myelosuppressive – L asparaginase § 4 -6 days - methotrexate § 5 -7 days cytarabine § 7 -10 days – doxorubicin*, mustargen, procarbazine § 10 days – mitoxantrone § 7 -14 days – chlorambucil*, cyclophosphamide** § 14 days – carboplatin (cats 17 21 days)

Side Effects Hair Loss § Fur might thin or change color, but complete hair loss is rare § Fur loss is more common with non shedding dogs such as poodles and terriers • Their fur continuously grows § Cats may lose guard hairs or whiskers

Don’t Whimp Out § 5 10% reduction in dose causes 30 50% reduction in efficacy § Clifford: THE DOSE IS THE DOSE § Underdosing is the single most common cause of poor responses or short remission § 2 nd most common cause is late treatments § STAY ON SCHEDULE!! Choose chemo clients carefully § The first remission is the best

Overdose § **Be very careful to use kg not lb when converting body weight to Body Surface Area** § Using lb will result in 2 x chemotherapy dose § If given PO, induce vomiting immediately, and then administer activated charcoal § This mistake is almost always fatal if given by injection Have 2 staff members calculate the dose, and

Overdose Thumb Rules § A 60 lb dog is about 1 m 2 § That dog would get: • • • 0. 5 0. 7 cc vincristine 15 cc doxorubicin 40 mg prednisone 50 60 mg CCNU 200 250 mg cyclophosphamide (8 10 small tablets, 4 5 large tablets • 1 vial Elspar

Patient Care § Chemotherapy patients should never be given MLV vaccines • risk of post vaccinal infection § Vaccinations with killed vaccines (rabies) should be fine § Clients should be furnished with gloves to wear • For administering chemo pills • for cleaning up pet eliminations • When sitting with animals during IV drips § Always provide a written educational handout for each drug given (http: //wendybount. com)

Response to Therapy § Complete Response (CR) no detectable tumor presence § Partial Response (PR) – 50%+ reduction in tumor size § Stable Disease (SD) <50% reduction or <25% increase in size, with no new tumors § Progressive Disease (PD) >25% increase in size or appearance of new masses or metastases § Median Survival Time (MST) – survival time at which 50% in the cohort are less than this value and 50% more § Progression Free Survival Time (PFST) – time from beginning treatment until first evidence of

Safe Handling § Order liquid injectables rather than those that must be reconstituted • Doxorubicin, vincristine, vinblastine, carboplatin, mitoxantrone § Have oral chemo doses professionally compounded § ALWAYS WEAR GLOVES!! • Chemo gloves or double latex gloves § Wear a respirator mask if you must reconstitute powders • Cytosar U, Actinomycin D, dacarbazine (not Elspar) § Inject bubbles out of the syringe prior to

Safe Handling § Reconstitute drugs in a biological safety cabinet • Have your local pharmacist do it for you, or Oncura § Use venting devices or drug filters to avoid aerosolization when withdrawing needle from the vial (Phaseal®) § Wear an isolation gown, buttoned lab coat, etc. § Wear eye protection § Oncology nurses have higher incidence of • • headaches and nausea Skin irritation Chromosomal, bone marrow and liver damage Miscarriage and cancer

Keep Refrigerated § § § § Doxorubicin Vincristine, Vinblastine L asparaginase Chlorambucil Cytarabine once reconstituted Dacarbazine Tanovea® None are damaged by refrigeration

MDR-1 Deletion White Feet – Don’t Treat § Increased sensitivity to some chemo drugs – reduce dose • Doxorubicin, D actinomycin, (Mitoxantrone) • Vincristine, Vinblastine • Paclitaxel § Which Dogs to test? • Susceptible breeds: (Client Handout on Testing) • adverse reaction to: • Vincristine or other chemo drugs on the list • higher than HWPrev doses of ivermectin, milbemycin, moxidectin, selamectin • Usual doses of loperamide, acepromazine, butorphanol,

MDR-1 Deletion § Test for MDR 1 deletion via online form http: //vcpl. vetmed. wsu. edu/ • EDTA blood submitted by vets • Cheek swab or blood test kits available to directly to clients • $60 per test if paid online; $70 if paid by check • If >5 animals on same form, $60 per animal any payment § Client Handout for affected dogs

MDR-1 Deletion § Do not give drugs that compete for p glycoprotein in the same week as chemotherapy • Spironolactone – Comfortis® or Trifexis® • Heart meds: Ca++ channel blockers (amioderone, diltiazem, verapamil, carvedilol); digoxin • Azole antifungals • Cyclosporine • Antibiotics: doxycycline: lincosamides (azithromycin, clarithromycin, erythromycin) • Opioids: buprenorphine, morphine, fentanyl

IV Push Chemotherapy § For drugs that are given IV quickly • Vincristine, mitoxantrone (vinblastine) § Flush butterfly catheter (19 22 gauge) with sterile fluid compatible with the drug • Place it on the glove envelope used as sterile field § Predraw syringes – two 4 6 cc fluid for flush, plus drug; remove needles and place on sterile field § Clip and gently clean the skin § Assistant occludes and rolls the vein, to release when instructed § Place butterfly catheter on clean stick, do not tape § Flush/test, inject drug, flush/test § Remove butterfly catheter and bandage leg

IV Drip Chemotherapy § For drugs that are given IV slowly – more than a minute or two • Doxorubicin, mustargen, actinomycin. D, carboplatin, (vinblastine) § Attach buretrol and IV line to compatible IV fluid bag and hang § Draw up chemo to be given § Clip and gently clean the skin § Place and secure IV catheter on clean stick

IV Drip Chemotherapy § Trained trusted assistant sits with dog during drip • If any problems, stop drip and then get help § Run 20 50 cc fluids into Buretrol and run into patient to test line patency • If problems, place another catheter § Add chemo drug to Buretrol and qs to 2 ml/minute • e. g. , doxorubicin given over 30 minutes, qs to 60 ml § Run 2 3 aliquots of 10 20 cc IV fluids into the buretrol and then into the patient, until fluid runs

Wicked Expensive Drugs § § § Cyclophosphamide (>$1, 000 per month)** Mustargen (<$700 for a 4 -pack)** Palladia® (>$500 a month for medium dog) Procarbazine (>$1000 last time I checked)** Doxil – liposomal doxorubicin – 20 x cost of doxorubicin § Zinecard® $750 for a 250 mg vial § Tanovea® $250 $750 per treatment Try Diamondback Pharmacy for all but TKIs Try Medshop Pharmacy in Longview

Alkylating Agents Orally or by IV injection or drip Efficacy not affected by route of administration § Cyclophosphamide (Cytoxan®, Neosar®) § Chlorambucil (Leukeran®) § Lomustine, aka CCNU (Ceenu®) § Melphalan (Alkeran®) § Mustargen (Mustine®) § Procarbazine (Matulane®) § Dacarbazine, (DTIC Dome®)

Cyclophosphamide § Dose: 200 250 mg/m 2 PO or IV • Can give in one dose, or divide into 3 5 daily doses § Indications: LSA, leukemias, carcinomas, sarcomas § Unique side effects: 1. Can cause sterile hemorrhagic cystitis (CIC) • Can predispose to transitional cell carcinoma • If not on prednisone, add furosemide 1 mg/lb given with each cyclophosphamide dose • Negative urine culture diagnoses CIC • If cystitis, discontinue and replace with chlorambucil • Give in the morning & encourage frequent bladder emptying 2. Give with food to prevent stomach upset

Cyclophosphamide § Unique side effects: • Rarely can cause pneumonitis • Cleared by liver and kidneys – use with caution in pets with liver or kidney disease • Very long term onset marrow suppression (months) § Drug Interactions: • Allopurinol an increase bone marrow toxicity • Doxorubicin can increase cardiotoxicity • Chloramphenicol, imipramine, phenobarbital, phenothiazines, KI, thiazide diuretics and vitamin A can enhance toxicity § Handling: Injectable is good for 14 days if refrigerated, once mixed (label says 6 days)

Chlorambucil § Dose: 15 20 mg/m 2 PO SID or QOD x 4 days, repeat q 3 weeks • If sterile cystitis in response to cyclophosphamide occurs, substitute chlorambucil 15 mg/m 2 PO SID x 4 days • 6 8 mg/m 2 PO QOD for chronic therapy in dogs & cats § Indications: leukemias, myeloma, indolent lymphomas § Unique Side Effects: Liver toxicity, Pneumonitis § Handling:

Lomustine § Dose: 60 70 mg/m 2 PO, q 3 4 weeks • Doses of 90 mg/m 2 are published, but Barton says she has never given this high dose without sepsis • Kevin Hahn uses 40 mg/m 2 every 2 weeks, Norseworthy for IBD • Premedicate with diphenhydramine § Indications: MCT, LSA Rescue, histiocytic sarcoma, CNS tumors, canine skin lymphoma § Unique Side effects: 1. Prolonged and cumulative myelosuppression • No other chemo for 3 4 weeks • First dose should have a 4 week treatment interval • If subsequent doses show recovery by 3 weeks, interval

Lomustine § Unique Side effects: 2. Can cause hepatotoxicity • • Serum panel prior to the first dose Bile acids if significant liver disease is suspected Choose another drug if bile acids significantly elevated Check panel prior to third dose and every other dose thereafter • Discontinue if and when ALT climbs or albumin falls significantly • Often discontinued after 6 12 doses • SAMe and silymarin may mediate hepatotoxicity 3. Eliminated by the kidneys Reduce dose in animals with kidney disease; possible renal toxicity 4. Give with food to reduce stomach upset

Antitumor Antibiotics by intravenous drip § Doxorubicin (Adriamycin®) § Mitoxantrone (Novantrone®) § Actinomycin D, dactinomycin (Cosmegen®) § Bleomycin § (Doxycycline) • Decreases metalloproteinases, which break down intracellular matrix allowing tumor invasion • Antioangiogenic effects

Doxorubicin – “Red Death” § Dose: 30 mg/m 2 IV over 20 minutes, q 2 3 weeks • Premedicate with diphenhydramine and Cerenia • 1 mg/kg if less than 15 kg, 25 mg/m 2 in cats § Indications: LSA, leukemia, carcinomas, sarcomas § Unique Side Effects: • Severe necrosis leading to amputation or death due to cardiotoxicity if extravasated • More likely to cause GI signs and malaise than the other drugs in CHOP protocols • Often the last drug to lose effectiveness in CHOP • Toxicity can be somewhat cumulative – may need to reduce dose with time

Doxorubicin – “Red Death” § Unique Side Effects: • Hypersensitivity – allergy to one brand may not be to others • Cardiotoxicity • Acute cardiotoxicity – cardiac arrest during or several hours after chemotherapy • Cumulative cardiotoxicity precludes further use of doxorubicin • can occur as low as 90 mg/m 2 total dose • 6% of dogs with 5+ doses • Nephrotoxicity in cats • monitor BUN, creat, phos • Urinalysis casts • Increased toxicity in dogs with MDR 1 Deletion

Doxorubicin – “Red Death” § Drug Interactions: • Actinomycin D and Ca channel blockers increase cardiotoxicity • Diltiazem • Verapamil • Cyclophosphamide, cyclosporine increase doxorubicin levels • Phenobarbital & glucosamine may reduce doxorubicin levels § Contraindications: • Myocardial failure • echocardiogram prior to giving doxorubicin to Dobermans, Great Danes and Boxers or if heart murmur • Dogs and Cats with renal failure

Doxorubicin – “Red Death” § Handling: • refrigerate and protect from light • Irritating to the skin – wash well if exposed § Special Client Communications: • Prior permission to take immediately to surgery if extravasated • Warn of cardiotoxicity – acute and cumulative • GET PERMISSION TO USE THIS DANGEROUS DRUG

Doxorubicin – “Red Death” § Lifetime Total Dose: • should not exceed 180 200 mg/m 2, unless cardioprotective drugs are given • Check echocardiogram prior to each dose >150 mg/m 2 • Should never exceed 240 mg/m 2, or cardiotoxicity is likely § Liposomal doxorubicin (Doxil) • Reduces cumulative cardiotoxicity • Can be used after total lifetime doxorubicin dose has been reached • Cost is 20 x that of native doxorubicin § Overcoming resistance with dacarbazine (see LSA Rescue Handout)

Doxorubicin Extravasation § Some believe you should take the dog right to surgery and cut out the red stuff § Give Zinecard (dexrazoxane) 150 300 mg/m 2 IV within 2 3 hrs of extravasation through a different IV catheter § Repeat at 24 and 48 hours § Zinecard can provide near 100% protection from slough and acute fatal cardiotoxicity § Ice pack 15 minutes every 6 hours for 48 hours § Apply DMSO 99% to area 2 x extravasation q 6 hrs x 14 days

Doxorubicin Extravasation

Doxorubicin Extravasation

Doxorubicin Extravasation 3 days post extravasation 6 days post extravasation

Doxorubicin Extravasation 12 days post extravasation 19 days post extravasation

Doxorubicin Extravasation 66 days post extravasation

Doxorubicin Extravasation Phil Bergman, DVM Flush the catheter prior to removing!

Mitoxantrone – “Blue Thunder” § Dose: 5 6. 5 mg/m 2 IV every 2 3 weeks § Indications: TCC, carcinomas • Safer for cats with renal failure than doxorubicin • Combining with dacarbazine (DTIC) may increase effectiveness for rescue therapy § Unique Side Effects: • • • Use with caution in hepatic disease Conjunctivitis Jaundice, renal failure Irritation if extravasated Green blue urine for up to 5 days

Mitoxantrone – “Blue Thunder” § Drug Interactions: • Increased dose of allopurinol may be needed • Enhanced cardiotoxicity if previous doxorubicin, daunorubicin or radiation therapy • Precipitates in contact with heparin § Contraindications: myocardial failure, though cardiotoxicity not yet reported in dogs as in people

Platinum Drugs by intravenous drip § Carboplatin (Paraplatin®) § Cisplatin

Carboplatin § Dose: • 300 350 mg/m 2 IV over 15 minutes q 3 weeks in dogs • 180 260 mg/m 2 IV over 15 minutes q 3 4 weeks in cats • Has been given intratumorally for nasal planum SCC in cats • Intracavitary for mesothelioma § Indications: carcinomas (not TCC), sarcomas, OK for cats § Unique Side Effects: • Anorexia or vomiting at 2 4 days • Used cautiously if hepatic or renal disease

Carboplatin § Drug Interactions: • increased nephrotoxicity and ototoxicity of aminoglycosides • Increased likelihood of MLV vaccine induced disease § Handling: • dilute in D 5 W, saline or sterile water • Once reconstituted, use within 8 hours • Black precipitate will form if it comes into contact with aluminum

Vinca Alkaloids by intravenous injection or drip § Vincristine (Oncovin®) § Vinblastine (Velban®)

Vincristine § Dose: 0. 5 0. 75 mg/m 2 IV push § Indications: LSA, leukemias, thrombocytopenia, TVT § Unique Side Effects: • Peripheral neuropathy ileus, constipation, dropped hocks • Slough if extravasated (not as severe as doxorubicin) • Infiltrate with dexamethasone or DMSO • Rare severe GI side effects in cats • Reduce dose by 50% if icteric (cats with LSA can be) • Use with caution with liver or musculoskeletal disease

Vincristine § Drug Interactions: • Toxicities increased by drugs that inhibit p glycoprotein • Comfortis or Trifexis • Ca++ channel blockers (amioderone, diltiazem, verapamil, carvedilol) • Azole antifungals • Cyclosporin • Lincosamides (azithromycin, clarithromycin, erythromycin) § Contraindications: severe liver disease § Handling: keep refrigerated

Vinblastine § Dose: 2 2. 2 mg/m 2 IV over 10 minutes • Nausea, pallor, vomiting if given too fast § Indications: LSA, MCT, carcinomas • Developed to avoid vincristine associated neuropathy (dogs) § Unique Side Effects: • More myelosuppressive than vincristine • The rest like vincristine • Nausea, vomiting for 24 hours § Drug Interactions/Contraindications: same as vincristine § Handling: keep refrigerated

Antimetabolites § Cytarabine, cytosine arabinoside (Cytosar U®) § Methotrexate § 5 Fluouracil

Corticosteroids by mouth or by injection § Prednisone § Dexamethasone

NSAIDs by mouth or by injection § Piroxicam (Feldene®) • Cancer cells express cyclo oxygenases that form prostaglandins • Prostaglandins of the E 2 series inhibit NK cells • NK cells kill cancer cells • COX 2 inhibitors and other COX inhibitors inhibit formation of the PGE 2 series • They remove inhibition of NK cells by cancer cells § Deramaxx® § Previcox®

Piroxicam – COX inhibitors § Dose: 0. 3 mg/kg PO SID to QOD • Little data, but some believe any COX inhibitor is just as good • Carprofen (Rimadyl®), meloxicam (Metacam®), Zubrin®, Onsior®, etc. • No studies of antineoplastic effects in cats § Indications: • carcinomas, sarcomas • Generally not LSA or MCT because those are on pred § Unique Side Effects: • Positive side effects – antipyretic, anti inflammatory, analgesic effects

Piroxicam – COX inhibitors § Unique Side Effects: • GI ulceration • Renal papillary necrosis – monitor especially in cats • peritonitis § Drug Interactions: • do not give with corticosteroids or furosemide • Displaces protein bound drugs to increase toxicity – aminoglycosides, anticoagulants, sulfas, phenytoin § Contraindications: serious toxicity when NSAIDs used with methotrexate

Enzymes § L Asparaginase (Elspar®) Compounded by KRS Global Validation Study

L-Asparaginase § MOA: • To make a cancer drug, some fundamental difference between cancer cells and normal cells must be defined and exploited • Lymphoproliferative tumors require huge amounts of asparagine to support tumor growth, and lack L asparaginase synthetase • Asparaginase is an enzyme that breaks down asparagine • Tumor cells become depleted and rapidly die § Dose: 10, 000 U/m 2 SC, IM, IV (max dose 1 vial) • Pretreat with diphenhydramine

L-Asparaginase § Unique Side Effects: • IV administration increases risk of anaphylaxis • Induction of hepatic encephalitis in patients with liver failure • Rare coagulopathy or hepatotoxicity • Hyperglycemia and dysregulation in diabetics • Thyroid suppression for 4 weeks § Drug Interactions: • Reduced efficacy of methotrexate (wait 48 hours) • Occasional marrow suppression when given with vincristine (separate by 2 3 days) § Contraindications: history of pancreatitis

L-Asparaginase § Handling: • no special handling is necessary as other chemo drugs • Keep refrigerated • Once reconstituted, good for 8 hours – 14 days • Discard turbid solutions • Dilute with D 5 W or sodium chloride – volume not crucial • Avoid shaking vigorously – becomes foamy and difficult to inject § Availability is intermittent • When in short supply, human oncologists get priority • Compounded products are sometimes available, with

Calculators § LSA Chemo Estimate Work Sheet § CHOP Dose Chart § Tanovea Dose Chart (see Lymphoma)

Hidden Slides § § § § Melphalan Mustargen Procarbazine Dacarbazine Actinomycin-D Cytarabine See NCT for TKI inhibitors (Palladia®)

Acknowledgements § Ruthanne Chun, BS, DVM, DACVIM(Oncology) UW Madison School of Vet Med, Madison, WI § Plumb Veterinary Drug Handbook, 7 th edition § Philip Bergman, DVM, MS, Ph. D, ACVIM (Oncology) Director, Clinical Studies (VCA) Oncologist, Ketonah Bedford Vet Center Bedford Hills, NY